Bone marrow stem cells have been used to treat a variety of diseases including leukemia, multiple myeloma, some types of lymphoma, graft versus host disease, and genetic disorders of the blood and immune system including aplastic anemia, sickle cell anemia, Severe Combined Immune Deficiency (SCID), Wiskott-Aldrich Syndrome (WAS), IPEX Syndrome, Hemophagocytic Lymphohistiocytosis (HLH), X-linked Lymphoproliferative Disease (XLP) and Chronic Granulomatous Disease (CGD). However, it is difficult and time-consuming to find a matching donor for a particular patient. Only a fraction of patients will find a suitable donor, and many patients die due to being unable to find a proper donor. In addition, finding a proper match is especially problematic for African-Americans, Hispanics, Native Americans and people of mixed ethnicity.
Hematopoietic stem cells (HSCs) are rare adult stem cells that have been identified in fetal bone marrow, fetal liver, aorta-gonad-mesonephros (AGM), umbilical cord blood (UCB), adult bone marrow, and peripheral blood, which are capable of differentiating into three cell lineages including myeloerythroid (red blood cells, granulocytes, monocytes), megakaryocyte (platelets) and lymphoid (T-cells, B-cells, and natural killer) cells. HSCs, like bone marrow stem cells, are used in clinical transplantation protocols to treat a variety of diseases including malignant and non-malignant disorders.
Sources of HSCs include bone marrow and peripheral blood. To obtain marrow cells, donors must undergo multiple aspirations to collect several thousand milliliters of bone marrow, a procedure that is carried out under general anesthesia. To collect HSCs from the peripheral blood, the donor must be treated with granulocyte colony-stimulating factor to increase the number of circulating HSCs. Both of these procedures entail some risk and significant cost. Another source of HSCs is umbilical cord blood (UCB). UCB has major advantages over other sources of HSCs, such as that from bone marrow and mobilized peripheral blood. Not only is UCB readily available from many of the nearly 50 UCB banks across the United States, it also shows increased tolerance for mismatches with the host major histocompatability complex (MEW). In addition to relative widespread availability, these HSCs have several useful properties, including their decreased ability to induce immunological reactivity. In many cases, use of UCB incurs significantly less graft-versus-host disease compared to other sources of HSCs.
One barrier to the use of UCB is limited HSC numbers per cord at harvest. As cell dose has been shown to be a major determinant of engraftment and survival after UCB transplantation, low stem cell numbers represents the most significant barrier to successful UCB stem cell transplantation. The ability to expand ex vivo, prior to transplantation, the stem cell components of a single cord blood unit will greatly increase the viability of this treatment modality. Infusing patients with larger numbers of stem cells as opposed the limited cells available in an unexpanded cord blood unit, should greatly increase the likelihood of successful engraftment.
Expansion of HSCs has remained an important goal to develop advanced cell therapies for bone marrow transplantation and many blood disorders. Despite the identification of several hematopoietic growth factors, only limited expansion of HSCs has been observed. There thus remains a need for new methods of expanding HSCs, particularly ex vivo methods.